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Review
. 2008 Oct 23;60(2):201-14.
doi: 10.1016/j.neuron.2008.10.004.

Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function

Gary J Bassell  1 , Stephen T Warren
Affiliations
Review

Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function

Gary J Bassell et al. Neuron. .

Abstract

Fragile X syndrome is the most common inherited form of cognitive deficiency in humans and perhaps the best-understood single cause of autism. A trinucleotide repeat expansion, inactivating the X-linked FMR1 gene, leads to the absence of the fragile X mental retardation protein. FMRP is a selective RNA-binding protein that regulates the local translation of a subset of mRNAs at synapses in response to activation of Gp1 metabotropic glutamate receptors (mGluRs) and possibly other receptors. In the absence of FMRP, excess and dysregulated mRNA translation leads to altered synaptic function and loss of protein synthesis-dependent plasticity. Recent evidence indicates the role of FMRP in regulated mRNA transport in dendrites. New studies also suggest a possible local function of FMRP in axons that may be important for guidance, synaptic development, and formation of neural circuits. The understanding of FMRP function at synapses has led to rationale therapeutic approaches.

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Figures

Figure 1
Figure 1. FMR1 Protein and Gene
(Top) Protein domains (green) and key residues (red). NLS, nuclear localization signal; KH1 and KH2, RNA-binding domains; NES, nuclear export signal; RGG, RGG box, RNA binding. I304N, naturally occurring FXS mutation abrogating polysome association; S499, primary phosphorylated serine. (Middle) FMR1 gene, coding exons (blue) and untranslated regions (gray). Exons coding for major protein domains are indicated as well as alternative splicing. (Bottom) 5′ untranslated CGG-repeat alleles. The common and intermediate normal alleles (<55 repeats) are indicated, as are the premutation carrier alleles (55–200 repeats) and the full-mutation FXS alleles (>200 repeats).
Figure 2
Figure 2. Visualization of Total and Phosphorylated FMRP in Dendrites and Spines
Immunofluorescence and 3D reconstruction of a cultured hippocampal neuron labeled for phosphorylated FMRP (red), total FMRP (blue), and F-actin using phalloidin (green). Colocalization of FMRP and phospho-FMRP within granules is shown in white. FMRP is transiently dephosphorylated by PP2A in response to mGluR activation to allow translation of FMRP-bound mRNAs (Narayanan et al., 2007).
Figure 3
Figure 3. Postsynaptic FMRP Signaling Model
Following stimulation of Gp1 mGluRs (green), inactive PP2A (gray) is immediately activated (green) and dephosphorylates FMRP (orange), rapidly allowing rapid translation of FMRP-associated mRNAs. Within 5 min, mTOR (blue) is activated via a homer cascade, inhibiting PP2A and activating S6K1 (red), leading to FMRP phosphorylation and possible translational inhibition of FMRP target messages. Simultaneously, mTOR activates translation in an FMRP-independent manner, triggering a sustained maintenance of translation. FMRP-dependent and -independent pathways control AMPA receptor internalization and other changes in synaptic function and spine morphology that contribute to mGluR-LTD. Based on Narayanan et al., 2007, , and references therein.
Figure 4
Figure 4. The Stimulated Travels and Function of FMRP throughout the Neuron
FMRP is in a complex with several translationally arrested mRNAs at the synapse. Following mGluR stimulation, FMRP-target mRNAs are rapidly derepressed, allowing for local translation. A second phase of FMRP-dependent plasticity is shown that involves the subsequent transport of new mRNAs from the cell body into dendrites. The model shown here illustrates translational repression at the level of elongation, as suggested by Ceman et al. (2003). The translational activation and repression of mRNA is regulated by a PP2A/S6K1 signaling module (Narayanan et al., 2007, 2008) (see Figure 3). (1) Upon mGluR1/5 activation, PP2A is rapidly activated and dephosphorylates FMRP, thereby allowing for (2) local translation of proteins that affect AMPAR trafficking, i.e., PSD-95, Arc, Map1b, and App (Westmark and Malter, 2007; Todd et al.,2003; Muddashetty et al., 2007; Hou et al., 2006;Davidkova and Carroll, 2007; Waung et al., 2008; Park et al., 2008). Following mGluR activation, FMRP is rephosphorylated by S6K1 with slower kinetics, leading to translational repression. (3) FMRP can also be ubiquitinated following mGluR stimulation, and its proteosome-dependent degradation is necessary for mGluR-LTD (Hou et al., 2006). The local degradation of FMRP may contribute to local protein synthesis underlying mGluR-LTD. A mechanism of local FMRP degradation may be balanced by its synthesis. FMRP is synthesized in synaptoneurosomes upon mGluR activation (Weiler et al., 1997), which may provide a feedback mechanism to restore translational repression. Upon mGluR stimulation, (4) there may be a retrograde signal that leads to the transport of new FMRP-associated mRNAs from the soma. The active bidirectional transport of FMRP granules in dendrites has recently been described (Dictenberg et al., 2008). This model speculates that FMRP itself may traffic from the synapse to the cell body and/or nucleus, where it may complex with new target mRNAs, and return to the activated synapse. (5) In that FMRP can shuttle into the nucleus (Eberhart et al., 1996), it will be interesting to assess whether nucleocytoplasmic trafficking is regulated by mGluR signaling. (6) FMRP has recently been shown to be necessary for the transport of several mRNAs into dendrites, whereas neurons cultured from Fmr1 KO mice show impaired mRNA transport dynamics (Dictenberg et al., 2008). This model speculates that the trafficking population of FMRP is phosphorylated; however, future work is needed to assess whether FMRP phosphorylation may influence mRNA trafficking.
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